Methods of treatment using a gastric retained gabapentin dosage

ABSTRACT

A method of treatment for epilepsy and other disease states is described, which comprises the delivery of gabapentin in a gastric retained dosage form.

BACKGROUND OF THE INVENTION

[0001] 1. Technical Field

[0002] The present invention relates to the use of gabapentin in agastric retained dosage form. More specifically, the invention relatesto the use of such dosage form to treat epilepsy and other diseasestates.

[0003] 2. Background

[0004] Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) is ananti-epileptic drug that is currently available in 100 mg, 300 mg and400 mg hard shell capsule as well as 600 mg and 800 mg tablet dosageforms, with recommended dosing of 900 mg to 1800 mg total daily dose inthree divided dosages. The oral bioavailability is dose-dependent, withapproximately 60% bioavailability for a dose in the range of 300-400 mg,but with only 35% bioavailability for a dose of 1600 mg (Bourgeois,Epilepsia 36 (Suppl. 5):S1-S7 (1995); Gram, Epilepsia 37 (Suppl.6):S12-S16 (1996)). The decrease in bioavailability with dose has beenattributed to carrier-mediated absorption (Stewart, et al.,Pharmaceutical Research 10(2):276-281 (1993).

[0005] In early work with rats, Vollmer, et al., Arzneim-Forsch/DrugResearch 36(1, Nr. 5):781-892 (1986) found that the absorption site forgabapentin was the duodenum. The absorption of gabapentin occursrelatively slowly with the peak plasma concentration occurringapproximately 2-6 hours after dosing (Bourgeois, supra). The eliminationof gabapentin is exclusively through renal pathways (Chadwick; TheLancet 343:89-91 (1994); Vollmer, supra; Thomson, et al., Clin.Pharmacokinet. 23(3):216-230 (1992); and Riva, et al., Clin.Pharmacokinet. 31(6):470-493 (1996)) with reported half-lives of 5-7hours (Chadwick, supra) and 6-7 hours (Gram, supra).

[0006] A once- or twice-daily dosage form of gabapentin would beexpected to improve compliance and therefore a controlled release dosageform has some distinct advantages over the conventional immediaterelease formulations. In addition, a controlled release dosage formwould lower the maximum plasma concentration, and this may result inreduced side effects. Since gabapentin is absorbed high in thegastrointestinal tract, by means of a saturable transport mechanism, agastric retained dosage form is particularly beneficial for delivery ofgabapentin since the dosage form would be able to keep the drug in theregion of absorption and show improved bioavailability by virtue of theslower release rate that avoids saturation of the carrier mediatedtransport of conventional dosages.

SUMMARY OF THE INVENTION

[0007] One aspect of the invention relates to a method of treatingepilepsy comprising administering a therapeutically effective amount ofgabapentin or a pharmaceutically acceptable salt thereof, in a gastricretained dosage form to a mammal in need of such treatment.

[0008] Yet another aspect of the invention relates to a method oftreating neuropathic pain comprising administering a therapeuticallyeffective amount of gabapentin or a pharmaceutically acceptable saltthereof, in a gastric retained dosage form to a mammal in need of suchtreatment.

[0009] Still another aspect of the invention relates to an improvedmethod of administering a therapeutically effective amount of gabapentinto a patient in need thereof, the improvement comprising administeringgabapentin or a pharmaceutically acceptable salt thereof, in a gastricretained dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010]FIG. 1 illustrates the dissolution profiles for three GRTMformulations; and

[0011]FIG. 2 illustrates the average plasma profile of three GRTMformulations and Nuerontin.

DESCRIPTION OF THE INVENTION

[0012] The invention relates to a method of treating a disease state,such as epilepsy, by administering gabapentin in a once- or twice-dailygastric retained dosage form. The gastric retained dosage form isparticularly beneficial for delivery of gabapentin due to its prolongedtransit in the upper gastrointestinal tract, which allows the drug to beabsorbed adequately in the preferred region of absorption. In addition,a gastric retained dosage form increases the t_(max) and allows for asmoother, more prolonged anti-spasmolytic effect. This dosage form alsolowers the C_(max) and may result in reduced incidence and/or severityof CNS side effects of the drug, such as somnolence, ataxia, fatigue anddizziness.

Method of Treatment

[0013] The instant invention is a method of treating a disease statecomprising administering a therapeutically effective amount ofgabapentin, or a pharmaceutically acceptable salt thereof, once- ortwice-daily in a gastric retained dosage form to a mammal in need ofsuch treatment. As used herein, the term “treating” covers treating thespecified disease in a mammal, particularly a human, and includes:

[0014] (i) preventing the disease from occurring in a subject which maybe predisposed to the disease but has not yet been diagnosed as havingit;

[0015] (ii) inhibiting the disease, i.e. arresting its development; or

[0016] (iii) relieving the disease, i.e. causing regression of thedisease.

[0017] One embodiment of the invention relates to an improved method ofadministering a therapeutically effective amount of gabapentin to apatient in need thereof, the improvement comprising administeringgabapentin or a pharmaceutically acceptable salt thereof, in a gastricretained dosage form.

[0018] Other embodiments of the invention relate to methods of treatingspecific disease states comprising administering a therapeuticallyeffective amount of gabapentin or a pharmaceutically acceptable saltthereof, in a gastric retained dosage form to a mammal in need of suchtreatment. Such methods find utility in treating numerous disease statesthat are currently being treated with conventional immediate releaseformulations of gabapentin and include, by way of illustration and notlimitation, epilepsy; neuropathic pain; psychiatric disorders such asbipolar disorder and panic disorder; movement disorders such as restlessleg syndrome, periodic movement disorder of sleep, essential tremor andacquired nystagmus; and prophylaxis of migraine headaches.

[0019] The invention also contemplates administering one or moreadditional therapeutic agents with the gabapentin treatment. Theselection of these additional therapeutic agents will depend upon thespecific disease state being treated, and are described in detail below.

Active Ingredient

[0020] The active ingredient in the method of the invention isgabapentin. Gabapentin is preferably used in the free amphoteric form.Pharmaceutically acceptable salt forms that retain the biologicaleffectiveness and properties of gabapentin and are not biologically orotherwise undesirable can also be used and may show superiorbioavailability. As used herein, the term “gabapentin” is intended toinclude the agent itself, as well as its pharmaceutically acceptablesalts.

[0021] Pharmaceutically acceptable salts may be amphoteric and may bepresent in the form of internal salts. Gabapentin may form acid additionsalts and salts with bases. Exemplary acids that can be used to formsuch salts include, by way of example and not limitation, mineral acidssuch as hydrochloric, hydrobromic, sulfuric or phosphoric acid ororganic acids such as organic sulfonic acids and organic carboxylicacids. Salts formed with inorganic bases include, for example, thesodium, potassium, lithium, ammonium, calcium, and magnesium salts.Salts derived from organic bases include, for example, the salts ofprimary, secondary and tertiary amines, substituted amines includingnaturally-occurring substituted amines, and cyclic amines, includingisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-dimethyl aminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, N-ethylpiperidine, fumarate, maleate,succinate, acetate and oxalate.

Additional Therapeutic Agents

[0022] The methods of the invention also contemplate the addition of oneor more therapeutic agents with the gabapentin treatment.

[0023] For those embodiments of the invention where the gabapentingastric retained dosage form is administered to treat epilepsy, suchadditional therapeutic agents can be other anti-epileptics oranticonvulsants, which include, by way of illustration and notlimitation, hydantoins, iminostilbenes, valproates, phenyltriazines,barbiturates, deoxybarbiturates, benzodiazepines and carbamates. Suchadditional agents are preferably hydantoins, iminostilbenes, valproatesor phenyltriazines.

[0024] The following examples of compounds within each of these classesis intended to be illustrative and not limiting in any manner. Examplesof suitable hydantoin anticonvulsants include ethotoin, fosphenytoin,mephenytoin, and, preferably, phenytoin. An examples of a suitableiminostilbene is carbamazepine. Examples of suitable valproates includevalprioic acid and sodium valproate. An exemplary suitablephenyltriazine is lamotrigene. A suitable barbiturate is phenobarbitaland an exemplary deoxybarbiturate is primidone. An example of a suitablebenzodiazepine is clorazepate. A suitable carbamate is felbamate.

[0025] For those embodiments of the invention where the gabapentingastric retained dosage form is administered to treat neuropathic pain,such additional therapeutic agents can be selected from the groupconsisting of other anticonvulsants, tricyclic antidepressants,levadopa, and opioids.

[0026] The following examples of compounds within each of these classesis intended to be illustrative and not limiting in any manner. Examplesof suitable anticonvulsants include carbamazepine, phenytoin andlamotrigine. Suitable tricyclic antidepressants include amitriptyline,imipramine, clomipramine and desipramine. Examples of suitable opioidsinclude oxycodone and tramadol.

[0027] For those embodiments of the invention where the gabapentingastric retained dosage form is administered to treat psychiatricdisorders, such additional therapeutic agents can be selected from thegroup consisting of lithium, carbamazepine, valproate, trifluoperazine,clonazepam, risperidone, lorazepam, venlafaxine, clozapine, olanzapine,benzodiazepines, neuroleptics, tricyclic antidepressants, selectiveserontin reuptake inhibitor (SSRI's), buprupion, and nefadone.

[0028] For those embodiments of the invention where the gabapentingastric retained dosage form is administered to treat bipolar disorder,such additional therapeutic agents can be selected from the groupconsisting of lithium, carbamazepine, valproate, trifluoperazine,clonazepam, risperidone, lorazepam, venlafaxine, clozapine, olanzapine,benzodiazepines, and neuroleptics.

[0029] For those embodiments of the invention where the gabapentingastric retained dosage form is administered to treat depression, suchadditional therapeutic agents can be selected from the group consistingof tri-cyclic anti-depressants, SSRI's, bupropion, venlaxatine, andnefadone.

[0030] For those embodiments of the invention where the gabapentingastric retained dosage form is administered to treat manic disorders,such additional therapeutic agents can be selected from the groupconsisting of diazepam, and oxazepam.

[0031] For those embodiments of the invention where the gabapentingastric retained dosage form is administered to treat movementdisorders, such additional therapeutic agents can be selected from thegroup consisting of benzodiazepines, dopaminergic agents, and opiates,particularly levodopa/carbidopa and clonazepam.

[0032] For those embodiments of the invention where the gabapentingastric retained dosage form is administered for prophylactic treatmentof migraine headaches, such additional therapeutic agents can beselected from the group consisting of tricyclic antidepressants(amitriptyline, doxepin, imipramine, maprotiline, protriptyline,desipramine), SSRI (fluoxetine), triptine (sumatriptan, etc.), andergotamine.

Dosage

[0033] In general, the term “therapeutically effective amount” refers tothat amount which is sufficient to effect treatment, when administeredto a mammal in need of such treatment. The therapeutically effectiveamount will vary depending on the subject being treated, the severity ofthe disease state and the manner of administration, and may bedetermined routinely by one of ordinary skill in the art.

[0034] In particular, for use in the treatment of epilepsy orneuropathic pain with a gastric retained dosage form, gabapentin may beused at doses appropriate for treating epilepsy or neuropathic pain withimmediate release dosage forms. However, the gastric retained dosageform is designed to provide for bioavailability of gabapentin at a levelgreater than or equal to 80% (>80%) relative to an equal dose of animmediate release dosage form. Typically, the method of the inventionwill involve administering gabapentin on a once- or twice-daily basisfor as long as the condition persists.

[0035] An effective dosage of gabapentin for the treatment of epilepsyis typically in the range of about 300-3600 mg/day, typically about900-2400 mg/day, more typically about 900-1800 mg/day.

[0036] An effective dosage of gabapentin for the treatment ofneuropathic pain is typically in the range of about 100-4800 mg/day,typically about 300-3600 mg/day, more typically about 900-2400 mg/day.

[0037] An effective dosage of gabapentin for the treatment ofpsychiatric disorders is typically in the range of about 100-4800mg/day, more typically about 900-3600 mg/day.

[0038] An effective dosage of gabapentin for the treatment of movementdisorders is typically in the range of about 100-4000 mg/day, typicallyabout 200-2700 mg/day, more typically about 500-2700 mg/day.

[0039] An effective dosage of gabapentin for the prophylactic treatmentof migraine headaches is typically in the range of about 200-4000mg/day, typically about 500-3600 mg/day, more typically about 900-2400mg/day.

Dosage Regimen

[0040] The methods of the invention provide a once- or twice-daily doseof the gabapentin gastric retained dosage form. The dosage can beadministered at any time, but it is preferred that the dosage isadministered at the same approximate time each day and in approximately12 hour intervals for the duration of treatment. In addition, it ispreferred that the gastric retained dosage form be taken with food, forexample with the morning or evening meals.

[0041] Accordingly, in one embodiment of the invention, gabapentin isadministered once-daily, for example, in the morning (e.g., upon risingor with the morning meal) or in the evening (e.g., with the evening mealor near bedtime).

[0042] In another embodiment of the invention, gabapentin isadministered twice-daily, for example, with the first dose being in themorning (e.g., upon rising or with the morning meal) and the second dosebeing in the evening (e.g., with the evening meal or near bedtime).

[0043] In another aspect of the invention, the method of administering atherapeutically effective amount of gabapentin in a gastric retaineddosage form further includes administering one or more additionaltherapeutic agents.

[0044] The additional therapeutic agents can be administered at the sametime or at a different time than the administration of gabapentin, andwill depend upon the nature of the disease being treated as well as theagent itself. For example, when the additional agent is anotheranti-epileptic, a twice-daily dose is sufficient and it may beadministered at the same time or at a different time than gabapentin.For purposes of facilitating patient compliance, administration of anyof the aforementioned additional agents at the same time is preferred.

Dosage Form

[0045] There are several drug delivery systems that are suitable for usein delivering gabapentin in the method of the invention as they areparticularly tailored to be gastric-retained dosages, such as theswellable bilayer described by Franz, et al., U.S. Pat. No. 5,232,704;the multi-layer tablet with a band described by Wong, et al., U.S. Pat.No. 6,120,803; the membrane sac and gas generating agent described inSinnreich, U.S. Pat. No. 4,996,058; the swellable, hydrophilic polymersystem described in Shell, et al., U.S. Pat. No. 5,972,389 and Shell, etal., WO 9855107; all of which are incorporated herein by reference.

[0046] Of particular interest are gastric retained dosage forms thatcontain hydrophilic polymers that swell to a size such that the dosageform is retained in the fed mode. For example, the gastric retaineddosage form can contain polymers with a high swelling capacity such aspolyethylene oxide, hydroxyethylcellulose andhydroxypropylmethylcellulose. The polymers are preferably of a moderateto high molecular weight (4×10³ to greater that 10⁷) to enhance swellingand provide control of the release of gabapentin. In one embodiment ofthe invention, a hydroxypropylmethylcellulose polymer of such molecularweight is utilized so that the viscosity of a 1% aqueous solution isabout 4000 cps to greater than 100,000 cps. An example of suitablepolyethylene oxide polymers are those having molecular weights(viscosity average) on the order of 2-7 million. A typical dosage formshould swell to approximately 115% of its original volume within onehour after administration, and at a later time should swell to a volumethat is 130% or more of the original volume. Fillers, binders,lubricants and other additives may also be included in the gastricretained dosage form, such as are well known to those of skill in theart.

[0047] A typical dosage form would provide for a drug delivery profilesuch that gabapentin both on an in vivo and in vitro basis, is deliveredfor at least 5 hours, and typically over a time period of about 8-10hours. In order to provide for sustained delivery, it is preferable thatat least 40 wt % of gabapentin is retained in the dosage form after 1hour, i.e., no more than 60 wt % of the drug is administered in thefirst hour. In addition, it may be desired to utilize a dosage form thatprovides for substantially all of the gabapentin to be delivered overthe intended duration, which is typically about 6-12 hours, wheresubstantially all is taken to mean at least about 85 wt % of thegabapentin is administered.

[0048] In one embodiment of the invention, the gastric retained dosageform of gabapentin is a capsule dosage form that allows for the extendedrelease of gabapentin in the stomach and comprises: (a) at least onecomponent that expands on contact with gastric juice and contains anagent capable of releasing carbon dioxide or nitrogen, gabapentin or apharmaceutically acceptable salt thereof; (b) at least one hydrophilicmembrane in the form of a sachet which contains component (a), expandsby inflation, floats on the aqueous phase in the stomach and ispermeable to gastric juice and; (c) capsule dosage form which containscomponents (a) and (b) and which disintegrates without delay in thestomach under the action of gastric juice. Component (a) may alsocontain a pharmaceutically acceptable hydrophilic swelling agent such aslower alkyl ethers of cellulose, starches, water-soluble aliphatic orcyclic poly-N-vinylamides, polyvinyl alcohols, polyacrylates,polymethacrylates, polyethylene glycols and mixtures thereof, as well asother materials used in the manufacture of pharmaceutical dosage forms.Further details regarding an example of this type of dosage form can befound in Sinnreich, U.S. Pat. No. 4,996,058.

[0049] In another embodiment of the invention, the gastric retaineddosage form of gabapentin is an extended release oral drug dosage formfor releasing gabapentin into the stomach, duodenum and small intestineof a patient, and comprises: a single or a plurality of solid particlesconsisting of gabapentin or a pharmaceutically acceptable salt thereofdispersed within a polymer that (i) swells unrestrained dimensionally byimbibing water from gastric fluid to increase the size of the particlesto promote gastric retention in the stomach of the patient in which thefed mode has been induced; (ii) gradually the gabapentin diffuses or thepolymer erodes over a time period of hours, where the diffusion orerosion commences upon contact with the gastric fluid; and (iii)releases gabapentin to the stomach, duodenum and small intestine of thepatient, as a result of the diffusion or polymeric erosion at a ratecorresponding to the time period. Exemplary polymers includepolyethylene oxides, alkyl substituted cellulose materials andcombinations thereof, for example, high molecular weight polyethyleneoxides and high molecular weight or viscosityhydroxypropylmethylcellulose materials. Further details regarding anexample of this type of dosage form can be found in Shell, et al., U.S.Pat. No. 5,972,389 and Shell, et al., WO 9855107.

[0050] In yet another embodiment, a bi-layer tablet releases gabapentinto the upper gastrointestinal tract from an active containing layer,while the other layer is a swelling or floating layer. Details of thisdosage may be found in Franz, et al., U.S. Pat. No. 5,232,704. Thisdosage form may be surrounded by a band of insoluble material asdescribed by Wong, et al., U.S. Pat. No. 6,120,803.

[0051] Another embodiment of the invention uses a gastric retainedswellable, sustained-release tablet having a matrix comprised ofpoly(ethylene oxide) and hydroxypropylmethylcellulose. This dosage formis illustrated in Example 1 and further details may be found in Gusler,et al., “Optimal Polymer Mixtures For Gastric Retentive Tablets,” filedon like date herewith and identified as Attorney Docket No.15662-001700US, the disclosure of which is incorporated herein byreference.

[0052] For those embodiments of the invention that include furtheradministering additional therapeutic agents simultaneously withgabapentin, these agents can either be administered in the gastricretained dosage form that includes gabapentin or can be administered ina dosage form that is separate from gabapentin. Exemplary dosage formsare described below.

Dosage Form of Additional Agents

[0053] For those embodiments of the invention that include furtheradministering one or more additional therapeutic agents, such dosagescan be any suitable formulation as are well known in the art. For thoseadditional agents where controlled release is desirable, the agent maybe incorporated in the gabapentin gastric retained dosage form or beadministered in a separate gastric retained or other controlled releaseformulation dosage form. For those additional agents where immediaterelease is desirable, the agent may be incorporated in a coating aroundthe gabapentin gastric retained dosage form or in a separate layer of abilayer tablet, the agent may be simply enclosed in the capsule of theaforementioned gabapentin gastric retained capsule dosage form, or theagent may be administered in a separate immediate release dosage form.

[0054] Typically, dosage forms contain the additional agent (anotheranti-epileptic or anticonvulsant agent) in combination with one or morepharmaceutically acceptable ingredients. The carrier may be in the formof a solid, semi-solid or liquid diluent, or a capsule. Usually theamount of active agent is about 0.1-95 wt %, more typically about 1-50wt %. Actual methods of preparing such dosage forms are known, or willbe apparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 18thEdition, 1990. The dosage form to be administered will, in any event,contain a quantity of the additional therapeutic agent(s) in an amounteffective to alleviate the symptoms of the subject being treated.

[0055] In the preparation of pharmaceutical formulations containing theadditional therapeutic agent in the form of dosage units for oraladministration the agent may be mixed with solid, powdered ingredients,such as lactose, microcrystalline cellulose, maltodextrin, saccharose,sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin,or another suitable ingredient, as well as with disintegrating agentsand lubricating agents such as magnesium stearate, calcium stearate,sodium stearyl fumarate and polyethylene glycol waxes. The mixture isthen processed into granules or pressed into tablets such as chewableand oral disintegrating tablets.

[0056] Soft gelatin capsules may be prepared by mixing the active agentand vegetable oil, fat, or other suitable vehicle. Hard gelatin capsulesmay contain granules of the active agent, alone or in combination withsolid powdered ingredients such as lactose, saccharose, sorbitol,mannitol, potato starch, corn starch, amylopectin, cellulose derivativesor gelatin.

[0057] Liquid preparations for oral administration may be prepared inthe form of syrups or suspensions, e.g. solutions or suspensionscontaining about 0.2-20 wt % of the active agent and the remainderconsisting of sugar or sugar alcohols and a mixture of ethanol, water,glycerol, propylene glycol and polyethylene glycol. If desired, suchliquid preparations may contain coloring agents, flavoring agents,saccharin and carboxymethyl cellulose or other thickening agents. Liquidpreparations for oral administration may also be prepared in the form ofa dry powder to be reconstituted with a suitable solvent prior to use.

[0058] When the method of the invention includes administering anotheranti-epileptic or an anticonvulsant agent, there are numerouscommercially available dosage forms that can be administered. Inaddition, other formulations can be readily designed based uponknowledge in the art, and include the gastric-retained delivery systemsdescribed above.

[0059] Typical dosage forms of the other anti-epileptics oranticonvulsants suitable for use in the invention include tablets,capsules, oral suspensions and syrup. One of skill in the art canreadily prepare one of these exemplary formulations or the otheranti-epileptic can be administered by means of one of the numerouscommercially available products, examples of which are provided below.

[0060] Commercially available hydantoin anticonvulsants include, forexample, Peganone® (ethotoin, Abbott); Mesantoin® (mephenytoin, Sandoz);and Dilantin® (phenytoin, Warner-Lambert).

[0061] Typical dosage forms of the antineuralgics suitable for use inthe invention include tablets, capsules and oral suspensions. One ofskill in the art can readily prepare one of these exemplary formulationsor the antineuralgic can be administered by means of one of the numerouscommercially available products, examples of which are provided below.

[0062] Commercially available antineuralgics include, for example,Atretol® (carbamazepine, Elan).

[0063] Although specific examples of suitable anti-epileptic,anticonvulsant agent and antineuralgic formulations are described above,it is understood that the invention is not limited to those examples asthere are numerous other formulations that can be used to deliver theother anti-epileptic or anticonvulsant agents.

[0064] The general methods of the invention are best understood withreference to the following examples which are intended to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. These examples are not intended, nor are they to beconstrued, as limiting the scope of the invention, but are merelyillustrative and representative thereof.

EXAMPLE 1

[0065] Tablets were manufactured using a dry blend process, and handmade on a Carver ‘Auto C’ Press (Fred Carver, Inc., Indiana). The dryblend process consisted of blending all of the ingredients in a plasticbag, and compressing into a 1000 mg tablet (600 mg gabapentin dose)using a 0.7086″×0.3937″ Mod Oval die (Natoli Engineering). Theparameters for the operation of the Carver ‘Auto C’ Press were asfollows: 4000 lbs. force, 0 second dwell time (the setting on the CarverPress), and 100% pump speed. Formulation Composition (wt %) PEO MethocelSample # Active Coagulant K100M M. St. 1 60.0 39.0 0.0 1 2 60.0 24.314.7 1 3 60.0 0.0 39.0 1

[0066] The dissolution was determined in USP apparatus 1 (40 meshbaskets), 100 rpm, in deionized water. Samples, 5 ml at each time-point,were taken without media replacement at 1, 4 and 8 hours.

[0067] The resulting cumulative dissolution profile, based upon atheoretical percent active added to the formulations is presented intabulated form below: Theoretical wt % of Active Released Time (hours)Sample 1 Sample 2 Sample 3 1 15.4 14.8 18.6 4 39.4 37.4 43.3 8 61.7 57.864.7

EXAMPLE 2

[0068] Tablets were manufactured using a dry blend process, and handmade on a Carver ‘Auto C’ Press (Fred Carver, Inc., Indiana). The dryblend process consisted of blending all of the ingredients in a plasticbag, and compressing into a 600 mg tablet (300 mg gabapentin) using a0.6299″×0.3937″ Mod Oval die (Natoli Engineering). The parameters forthe operation of the Carver ‘Auto C’ Press were as follows: ˜2000-2500lbs. force, 0 second dwell time (the setting on the Carver Press), and100% pump speed. Formulation Composition (wt %) PEO Methocel Sample #Active Coagulant K15M M. St. 4 50.0 24.5 24.50 1

[0069] The dissolution was determined in USP apparatus 1 (40 meshbaskets), 100 rpm, in deionized water. Samples, 5 ml at each time-point,were taken without media replacement at 1, 2, 4 and 8 hours. Theresulting cumulative dissolution profile, based upon a theoreticalpercent active added to the formulation is presented in tabulated formbelow: Theoretical wt % of Active Released Time (hours) Sample A 1 20.62 32.4 4 49.7 6 63.1 8 74.0 10 82.6

EXAMPLE 3

[0070] Three Gstric Retentive (GR™) gabapentin formulas weremanufactured utilizing a standard granulation technique. Theformulations manufactured are shown in tabulated form below. Formulationfor Clinical Trial Manufacture Gabapentin GR8, 300- Gabapentin GR6, 300-Gabapentin GR8, 600- mg (GR8, 300-mg) mg (GR6, 300-mg) mg (GR8, 600-mg)44.76% Gabapentin 44.76% Gabapentin 61.11% Gabapentin 21.99% Methocel ®16.46% Methocel ®  7.59% Methocel ® K15M, premium K4M, premium K15M,premium 21.99% Sentry ® 21.99% Sentry ® 27.09% Sentry ® PolyOx ® WSRPolyOx ® WSR 303, PolyOx ® WSR 303, Coagulant, NF FP NF FP NF FP  7.49%Avicel ® 12.98% Avicel ® PH-  0.00% Avicel ® PH- PH-101, NF 101, NF 101,NF  2.75% Methocel ®  2.75% Methocel ® E5,  3.22% Methocel ® E5, prem.prem. E5, prem.  1.00% Magnesium  1.00% Magnesium  1.00% MagnesiumStearate, NF Stearate, NF Stearate, NF 670-mg (Tablet 670-mg (Tabletweight) 982-mg (Tablet weight) weight) 0.3937″ × 0.6299″ 0.3937″ ×0.6299″ 0.4062″ × 0.75″ Mod Oval Mod Oval Mod Cap

[0071] Gabapentin was obtained from Plantex U.S.A. (Englewood Cliffs,N.J.). Methocel® brand hydroxypropyl methylcellulose (also known ashypromellose), and Sentry® PolyOx® brand polyethylene oxide wereobtained from Dow Chemical (Midland, Mich.). Methocel E5, premium is aUSP type 2910 hydroxypropyl methylcellulose with number averagemolecular weight of on the order of 6000-8000 and a viscosity of 5 cpsas a 2% aqueous solution at 20 C. Methocel® K4M and Methocel® K15M areUSP type 2208 hydroxypropyl methylcellulose with viscosities of 4000 cpsand 15,000 cps, respectively, as a 2% aqueous solution at 20 C, andnumber average molecular weights on the order of 80,000 and 100,000,respectively. Sentry PolyOx® WSR 301, NF FP, Sentry® PolyOx® WSRCoagulant, NF FP and Sentry® PolyOx® WSR 303, NF FP haveviscosity-average molecular weights of approximately 4,000,000,5,000,000 and 7,000,000, respectively. Avicel PH-101, NF ismicrocrystalline cellulose supplied by FMC Corporation (Philadelphia,Pa.). Magnesium stearate, NF was supplied by Spectrum Quality Products(New Brunswick, N.J.).

[0072] The dissolution profiles, as determined by USP Apparatus I (100rpm) in modified simulated gastric fluid, for three prototypes GR™formulations are shown in FIG. 1.

EXAMPLE 4

[0073] The pharmacokinetic profiles of the three formulations describedin Example 3, administered as a 600-mg dose, were compared to Neurontin®immediate release 300-mg capsule in a randomized four-way cross-overexperiment involving 15 healthy volunteers. Each subject wasadministered treatment of 600-mg gabapentin as one of the three GR™formulations (1×600-mg tablet or 2×300-mg tablet) or Neurontin® capsules(2×300-mg) within 5 minutes of completing a high fat breakfast (FDAbreakfast). Plasma samples were taken up to 48 hours post-dose. FIG. 2illustrates the average plasma profile for the four treatmentsadministered, and the pharmacokinetic data are summarized in tabulatedform below. Gabapentin Plasma Data - Average for 15 Subjects AUC_(inf)^(#) C_(max) ^(#) Dosing ((ug/ml)*hr) (ug/ml) T_(max) (hours)Neurontin ®, 300-mg Mean: 46.65 4.72 3.93 2 × capsules % CV: 19.0 20.215.1 GR6, 300-mg Mean: 44.43 2.97 6.63 2 × tablets % CV: 34.9 29.7 45.1GR8, 300-mg Mean: 41.84 3.10 5.63 2 × tablets % CV: 34.4 26.2 34.9 GR8,600-mg Mean: 48.01 3.13 7.13 1 × tablet % CV: 26.8 18.7 42.2

[0074] As demonstrated in FIG. 2 and in tabulated form above, GR™formulations demonstrate sustained release with a lower maximum plasmaconcentration and a larger value for the time of the maximumconcentration compared to the immediate release capsules without loss inthe bioavailability as measured by the plasma AUC_(inf).

[0075] Each of the patent applications, patents, publications, and otherpublished documents mentioned or referred to in this specification isherein incorporated by reference in its entirety, to the same extent asif each individual patent application, patent, publication, and otherpublished document was specifically and individually indicated to beincorporated by reference.

[0076] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A method of treating epilepsy comprisingadministering a therapeutically effective amount of gabapentin or apharmaceutically acceptable salt thereof, in a gastric retained dosageform to a mammal in need of such treatment.
 2. The method of claim 1wherein the dosage form is administered once-daily.
 3. The method ofclaim 2 wherein the dosage form is administered with a meal.
 4. Themethod of claim 1 wherein the dosage form is administered twice-daily.5. The method of claim 4 wherein each dosage form is administered with ameal.
 6. The method of claim 1 which further comprises administering oneor more additional anti-epileptics or anticonvulsants.
 7. The method ofclaim 1 wherein the dosage form is administered once- or twice-daily andthe total amount of gabapentin in the daily dosage is about 200-4000 mg.8. The method of claim 7 wherein the total amount of gabapentin in thedaily dosage is about 600-2700 mg.
 9. The method of claim 8 whereintotal amount of gabapentin in the daily dosage is about 900-1800 mg. 10.The method of claim 1 wherein the dosage form is an extended releaseoral drug dosage form for releasing gabapentin into the stomach,duodenum and small intestine of the mammal.
 11. The method of claim 10wherein gabapentin is administered from the dosage form for a period ofat least 5 hours and at least 40 wt % of the gabapentin is retained inthe dosage form after 1 hour.
 12. The method of claim 11 wherein thedosage form provides administration of at least 80 wt % of thegabapentin to be delivered over a period of about 5-12 hours.
 13. Themethod of claim 11 wherein the dosage form contains at least onehydrophilic polymer that swells to an extent such that it promotesgastric retention of the dosage form in the fed mode.
 14. The method ofclaim 13 wherein the polymer is selected from the group consisting ofpolyethylene oxides, alkyl substituted cellulose materials, andcombinations thereof.
 15. The method of claim 11 wherein the dosage formfurther comprises a gas generating agent.
 16. The method of claim 15wherein the gabapentin is contained in a membrane sachet with the gasgenerating agent.
 17. The method of claim 1 wherein the dosage form isan adhesive tablet.
 18. The method of claim 1 wherein the dosage form isa film coated dosage form or a capsule dosage form that allows for theextended release of gabapentin in the stomach duodenum and smallintestine of the mammal.
 19. The method of claim 1 wherein the dosageform is a swellable, sustained-release tablet having a matrix comprisedof poly(ethylene oxide) and hydroxypropylmethylcellulose.
 20. A methodof treating neuropathic pain comprising administering a therapeuticallyeffective amount of gabapentin or a pharmaceutically acceptable saltthereof, in a gastric retained dosage form to a mammal in need of suchtreatment.
 21. The method of claim 20 wherein the dosage form isadministered once-daily.
 22. The method of claim 21 wherein the dosageform is administered with a meal.
 23. The method of claim 20 wherein thedosage form is administered twice-daily.
 24. The method of claim 23wherein each dosage form is administered with a meal.
 25. The method ofclaim 20 which further comprises administering one or more therapeuticagents selected from the group consisting of anticonvulsants, tricyclicantidepressants, opioids, and levodopa.
 26. The method of claim 20wherein the dosage form is administered once- or twice-daily and thetotal amount of gabapentin in the daily dosage is about 100-4800 mg. 27.The method of claim 26 wherein the total amount of gabapentin in thedaily dosage is about 300-3600 mg.
 28. The method of claim 27 whereinthe total amount of gabapentin in the daily dosage is about 900-2400 mg.29. The method of claim 20 wherein the dosage form is an extendedrelease oral drug dosage form for releasing gabapentin into the stomach,duodenum and small intestine of the mammal.
 30. The method of claim 29wherein gabapentin is administered from the dosage form for a period ofat least 5 hours and at least 40 wt % of the gabapentin is retained inthe dosage form after 1 hour.
 31. The method of claim 30 wherein thedosage form provides administration of at least 85 wt % of thegabapentin to be delivered over a period of about 5-12 hours.
 32. Themethod of claim 30 wherein the dosage form contains at least onehydrophilic polymer that swells to an extent such that it promotesgastric retention of the dosage form in the fed mode.
 33. The method ofclaim 32 wherein the polymer is selected from the group consisting ofpolyethylene oxides, alkyl substituted cellulose materials, andcombinations thereof.
 34. The method of claim 30 wherein the dosage formfurther comprises a gas generating agent.
 35. The method of claim 34wherein the gabapentin is contained in a membrane sachet with the gasgenerating agent.
 36. The method of claim 20 wherein the dosage form isan adhesive tablet.
 37. The method of claim 20 wherein the dosage formis a film coated dosage form or a capsule dosage form that allows forthe extended release of gabapentin in the stomach duodenum and smallintestine of the mammal.
 38. The method of claim 20 wherein the dosageform is a swellable, sustained-release tablet having a matrix comprisedof poly(ethylene oxide) and hydroxypropylmethylcellulose.
 39. A methodof treating psychiatric disorders comprising administering atherapeutically effective amount of gabapentin or a pharmaceuticallyacceptable salt thereof, in a gastric retained dosage form to a mammalin need of such treatment.
 40. The method of claim 39 wherein thepsychiatric disorder is bipolar disorder or panic disorder.
 41. Themethod of claim 39 wherein the dosage form is administered once-daily.42. The method of claim 41 wherein the dosage form is administered witha meal.
 43. The method of claim 39 wherein the dosage form isadministered twice-daily.
 44. The method of claim 43 wherein each dosageform is administered with a meal.
 45. The method of claim 39 whichfurther comprises administering one or more therapeutic agents selectedfrom the group consisting of anticonvulsants, tricyclic antidepressants,opioids, and levodopa.
 46. The method of claim 39 wherein the dosageform is administered once- or twice-daily and the total amount ofgabapentin in the daily dosage is about 100-4800 mg.
 47. The method ofclaim 46 wherein the total amount of gabapentin in the daily dosage isabout 900-3600 mg.
 48. The method of claim 39 wherein the dosage form isan extended release oral drug dosage form for releasing gabapentin intothe stomach, duodenum and small intestine of the mammal.
 49. The methodof claim 48 wherein gabapentin is administered from the dosage form fora period of at least 5 hours and at least 40 wt % of the gabapentin isretained in the dosage form after 1 hour.
 50. The method of claim 49wherein the dosage form provides administration of at least 85 wt % ofthe gabapentin to be delivered over a period of about 5-12 hours. 51.The method of claim 49 wherein the dosage form contains at least onehydrophilic polymer that swells to an extent such that it promotesgastric retention of the dosage form in the fed mode.
 52. The method ofclaim 51 wherein the polymer is selected from the group consisting ofpolyethylene oxides, alkyl substituted cellulose materials, andcombinations thereof.
 53. The method of claim 49 wherein the dosage formfurther comprises a gas generating agent.
 54. The method of claim 53wherein the gabapentin is contained in a membrane sachet with the gasgenerating agent.
 55. The method of claim 39 wherein the dosage form isan adhesive tablet.
 56. The method of claim 39 wherein the dosage formis a film coated dosage form or a capsule dosage form that allows forthe extended release of gabapentin in the stomach.
 57. The method ofclaim 39 wherein the dosage form is a swellable, sustained-releasetablet having a matrix comprised of poly(ethylene oxide) andhydroxypropylmethylcellulose.
 58. A method of treating movementdisorders comprising administering a therapeutically effective amount ofgabapentin or a pharmaceutically acceptable salt thereof, in a gastricretained dosage form to a mammal in need of such treatment.
 59. Themethod of claim 58 wherein the movement disorder is restless legsyndrome, periodic movement disorder of sleep, essential tremor oracquired nystagmus.
 60. The method of claim 58 wherein the dosage formis administered once-daily.
 61. The method of claim 60 wherein thedosage form is administered with a meal.
 62. The method of claim 58wherein the dosage form is administered twice-daily.
 63. The method ofclaim 62 wherein each dosage form is administered with a meal.
 64. Themethod of claim 58 which further comprises administering one or moretherapeutic agents selected from the group consisting ofanticonvulsants, tricyclic antidepressants, opioids, benzodiazepine, anddopaminergic agents.
 65. The method of claim 58 wherein the dosage formis administered once- or twice-daily and the total amount of gabapentinin the daily dosage is about 100-4000 mg.
 66. The method of claim 65wherein the total amount of gabapentin in the daily dosage is about200-3000 mg.
 67. The method of claim 66 wherein the total amount ofgabapentin in the daily dosage is about 500-2700 mg.
 68. The method ofclaim 58 wherein the dosage form is an extended release oral drug dosageform for releasing gabapentin into the stomach, duodenum and smallintestine of the mammal.
 69. The method of claim 68 wherein gabapentinis administered from the dosage form for a period of at least 5 hoursand at least 40 wt % of the gabapentin is retained in the dosage formafter 1 hour.
 70. The method of claim 69 wherein the dosage formprovides administration of at least 80 wt % of the gabapentin to bedelivered over a period of about 5-12 hours.
 71. The method of claim 69wherein the dosage form contains a hydrophilic polymer that swells to asize such that the dosage form is retained in the fed mode.
 72. Themethod of claim 71 wherein the polymer is selected from the groupconsisting of polyethylene oxides, alkyl substituted cellulosematerials, and combinations thereof.
 73. The method of claim 69 whereinthe dosage form further comprises a gas generating agent.
 74. The methodof claim 73 wherein the gabapentin is contained in a membrane sachetwith the gas generating agent.
 75. The method of claim 58 wherein thedosage form is an adhesive tablet.
 76. The method of claim 58 whereinthe dosage form is a film coated dosage form or a capsule dosage formthat allows for the extended release of gabapentin in the stomach. 77.The method of claim 58 wherein the dosage form is a swellable,sustained-release tablet having a matrix comprised of poly(ethyleneoxide) and hydroxypropylmethylcellulose.
 78. A method for theprophylactic treatment of migraine headaches comprising administering atherapeutically effective amount of gabapentin or a pharmaceuticallyacceptable salt thereof, in a gastric retained dosage form to a mammalin need of such treatment.
 79. The method of claim 78 wherein the dosageform is administered once-daily.
 80. The method of claim 79 wherein thedosage form is administered with a meal.
 81. The method of claim 78wherein the dosage form is administered twice-daily.
 82. The method ofclaim 81 wherein each dosage form is administered with a meal.
 83. Themethod of claim 78 which further comprises administering one or moretherapeutic agents selected from the group consisting ofanticonvulsants, tricyclic antidepressants, opioids, and levodopa. 84.The method of claim 78 wherein the dosage form is administered once- ortwice-daily and the total amount of gabapentin in the daily dosage isabout 200-4000 mg.
 85. The method of claim 84 wherein the total amountof gabapentin in the daily dosage is about 500-3600 mg.
 86. The methodof claim 85 wherein the total amount of gabapentin in the daily dosageis about 900-2400 mg.
 87. The method of claim 78 wherein the dosage formis an extended release oral drug dosage form for releasing gabapentininto the stomach, duodenum and small intestine of the mammal.
 88. Themethod of claim 87 wherein gabapentin is administered from the dosageform for a period of at least 5 hours and at least 40 wt % of thegabapentin is retained in the dosage form after 1 hour.
 89. The methodof claim 88 wherein the dosage form provides administration of at least85 wt % of the gabapentin to be delivered over a period of about 5-12hours.
 90. The method of claim 88 wherein the dosage form contains atleast one hydrophilic polymer that swells to an extent such that itpromotes gastric retention of the dosage form in the fed mode.
 91. Themethod of claim 90 wherein the polymer is selected from the groupconsisting of polyethylene oxides, alkyl substituted cellulosematerials, and combinations thereof.
 92. The method of claim 88 whereinthe dosage form further comprises a gas generating agent.
 93. The methodof claim 92 wherein the gabapentin is contained in a membrane sachetwith the gas generating agent.
 94. The method of claim 78 wherein thedosage form is an adhesive tablet.
 95. The method of claim 78 whereinthe dosage form is a film coated dosage form or a capsule dosage formthat allows for the extended release of gabapentin in the stomachduodenum and small intestine of the mammal.
 96. The method of claim 78wherein the dosage form is a swellable, sustained-release tablet havinga matrix comprised of poly(ethylene oxide) andhydroxypropylmethylcellulose.
 97. An improved method of administering atherapeutically effective amount of gabapentin to a patient in needthereof, the improvement comprising administering gabapentin or apharmaceutically acceptable salt thereof, in a gastric retained dosageform.
 98. The method of claim 97 wherein the dosage form is administeredonce-daily.
 99. The method of claim 98 wherein the dosage form isadministered with a meal.
 100. The method of claim 97 wherein the dosageform is administered twice-daily.
 101. The method of claim 100 whereineach dosage form is administered with a meal.
 102. The method of claim97 where the patient is being treated for epilepsy.
 103. The method ofclaim 97 where the patient is being treated for neuropathic pain. 104.The method of claim 97 where the patient is being treated forpsychiatric disorders.
 105. The method of claim 97 where the patient isbeing treated for movement disorders.
 106. The method of claim 97 wherethe patient is receiving prophylactic treatment for migraine headaches.107. The method of claim 97 wherein the dosage form is an extendedrelease oral drug dosage form for releasing gabapentin into the stomach,duodenum and small intestine of the mammal.
 108. The method of claim 107wherein gabapentin is administered from the dosage form for a period ofat least 5 hours and at least 40 wt % of the gabapentin is retained inthe dosage form after 1 hour.
 109. The method of claim 108 wherein thedosage form provides administration of at least 80 wt % of thegabapentin to be delivered over a period of about 5-12 hours.
 110. Themethod of claim 108 wherein the dosage form contains at least onehydrophilic polymer that swells to an extent such that it promotesgastric retention of the dosage form in the fed mode.
 111. The method ofclaim 110 wherein the polymer is selected from the group consisting ofpolyethylene oxides, alkyl substituted cellulose materials, andcombinations thereof.
 112. The method of claim 108 wherein the dosageform further comprises a gas generating agent.
 113. The method of claim112 wherein the gabapentin is contained in a membrane sachet with thegas generating agent.
 114. The method of claim 97 wherein the dosageform is an adhesive tablet.
 115. The method of claim 97 wherein thedosage form is a film coated dosage form or a capsule dosage form thatallows for the extended release of gabapentin in the stomach.
 116. Themethod of claim 97 wherein the dosage form is a swellable,sustained-release tablet having a matrix comprised of poly(ethyleneoxide) and hydroxypropyl methylcellulose.